Evidence that aberrant protein metabolism contributes to chemoresistance in multiple myeloma cells.

Multiple myeloma (MM) is an incurable B lymphocyte cancer. To date, a comparative analysis of global protein metabolism for the MM cell line CCL-155 (RPMI-8226) and the non-cancerous B lymphocyte cell line CCL-156 (RPMI‑1788) has not been published. Here, we report that both global protein synthesis and degradation occur at a higher rate in MM cells and demonstrate that alkylating agents can reduce global protein degradation in both cell lines, but the effect is greater in CCL-156 cells. Treatment with melphalan plus the proteasome inhibitor MG132 reduced global protein degradation for MM cells to roughly 60% of that seen without drugs, but the reduction was approximately three times greater for CCL-156 cells. This drug combination was growth inhibitory for both cell lines, but CCL-156 inhibition was 2-fold greater than that of the MM cell line. Additionally, treatment with melphalan plus the lysosomal inhibitor chloroquine did not affect growth of MM cells more than melphalan alone, whereas this combination drastically inhibited growth of CCL-156 cells despite protein degradation being maintained at 60% level for both cell lines. This suggests that a lysosomal function other than protein degradation is required for recovery from alkylation damage in CCL-156 cells. In general, CCL-156 cells were affected to a greater extent for both protein degradation and growth inhibition with most drug combinations tested. Statistical analysis of our data (p=0.066) provides evidence that aberrant proteasome-mediated protein degradation correlates with chemoresistance in MM cells, but that lysosome-mediated protein degradation does not.